Men with advanced prostate cancer are typically treated with hormonal therapy, which leads to tumour shrinkage. However, tumours relapse and develop into the lethal form of the disease, termed castration-resistant prostate cancer (CRPC). Two distinct, but not mutually exclusive, models have been proposed in the literature to describe the onset of CRPC: adaptation and selection. Although some studies indicate that tumour cells acquire new alterations that enable them to survive in the castrated state (adaptation), other research points to the outgrowth of rare, pre-existing cells capable of surviving hormonal therapy (selection). Targeting the cells that survive hormonal therapy--by either adaptation or selection--is necessary to prevent the development of CRPC. Current research is focused on not only understanding the cellular mechanisms of CRPC, but also defining critical pathways that can be targeted with combinatorial therapies in castration-resistant cancer cells.